Huntington's disease (HD) is an autosomal dominant disorder caused by a mutation in the IT15 gene encoding the protein huntingtin (htt). The mutation consists of an expanded polyglutamine region characterized by CAG repeats (The Huntington's Disease Collaborative Research Group, 1993), and the protein is expressed throughout the nervous system and periphery. The medium size spiny neuron (MSN) of the striatum is the most vulnerable cell in this disease. Current areas of research focus include the etiology of neuronal dysfunction, i.e. transcriptional dysregulation, which appears to precede neuronal death, and the determination of whether the pathophysiology is cell-autonomous. Thus, open questions include :) Is expression of mutant huntingtin in striatal neurons sufficient to produce MSN dysfunction and/or death? And 2) Is down-regulation of striatal-enriched proteins in the presence of mutant htt related to a cell-specific transcriptional mechanism? Using a unique reagent, the recently identified fragment of the DARPP-32 promoter (D9) that restricts transgene expression in the forebrain to the MSNs of the striatum. the Aims of the proposed project are: Specific Aim 1: To produce transgenic mouse models of Huntington's disease with striatal-specific expression of mutant htt, either Exon 1, or full-length, and Specific Aim 2: To determine if D9/LacZ is transcriptionally down-regulated in the presence of mutant htt. This will be accomplished by crossing of the already established D9/LacZ mouse with the R6/2 HD mouse model, in which endogenous DARPP-32 is down-regulated.